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616
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1976 by The Williams & Wilkins Co.Vol. 196, No. 3
Printed in U.S.A.
THE EFFECTS OF PHENCYCLIDINE, KETAMINE,
d-AMPHETAMINE AND PENTOBARBITAL ON
SCHEDULE-CONTROLLED BEHAVIOR IN
THE MOUSE” 2
GALEN R. WENGER AND P. B. DEWS
Laboratory of Psychobiology, Harvard Medical School, Boston, Massachusetts
Accepted for publication October 20, 1975
ABSTRACT
WENGER, GALEN R. AND P.B. DEWS: The effects of phencyclidine, ketamine,
d-amphetamine and pentobarbital on schedule-controlled behavior in the mouse.
J. Pharmacol. Exp. Ther. 196: 616-624, 1976.
The response of mice of breaking a light beam onto a photocell was programmed to
produce food according to a multiple schedule with alternating 30-response fixed ratio,
300-second fixed interval (FR-30 FI-300 sec) components. Training was standardized
for all mice, and stable patterns of responding that were similar to those described for
other species and responses under this schedule developed quickly. The effects of
pentobarbital, d-amphetamine, phencyclidine and ketamine were studied. At some
dose, each of the four drugs produced an increase in rate of responding; the increase was
proportionately greater at low rates of responding than at higher rates. At some dose
range, d-amphetamine, ketamine and phencyclidine produced dose-related increases
in Fl response rates but only decreases in FR response rates. The maximum increases in
Fl average rates were to 1.83, 1.25 and 1.32 times the control rate for d-amphetamine (1
mg/kg), ketamine (100 mg/kg) and phencyclidine (3 mg/kg), respectively. Phencycli-
dine and ketamine thus showed some “amphetamine-like” effects in the mouse.
Pentobarbital increased (1.25 times the control rate) both the FR and Fl response rates
at a dose of 3 mg/kg. Higher doses of pentobarbital progressively decreased both FR
and Fl response rates in a parallel fashion.
Phencyclidine hydrochloride (PCD) and ke-
tamine hydrochloride (KT) can change the
behavior of laboratory animals at subanesthetic
doses. Increases in spontaneous locomotor ac-
tivity are observed in mice and rats after low
Received for publication June 16, 1975.
‘This investigation was supported by U.S. PublicHealth Service Grants MH 07084, MH 02094, MH07658 and MH 00499.
2A preliminary abstract of the study appears inFed. Proc. (34: 766Abs, 1975).
doses of PCD or KT (Chen et a!., 1959, 1966;
Hittzemann et a!., 1973), an effect that is
enhanced by pretreatment with iproniazid
(Chen et a!., 1965). The same studies report a
“calming” effect in pigeons, guinea pigs, ham-
sters, cats, dogs and monkeys after low doses of
PCD or KT and a state of immobility at higher
doses.
At present, there is little information on the
effect of PCD or KT on schedule-controlled
(operant) behavior. Previous work in this labo-
ratory (Wenger, 1976) has shown PCD and KT
to have effects qualitatively like those of am-
phetamine on a multiple schedule of food pres-
1976 PHENCYCLIDINE, KETAMINE AND BEHAVIOR 617
FIG. 1. A diagram of the experimental chamber used for mice (see text for further details).
entation in the pigeon, with alternating 30-
response fixed ratio and 600-second fixed inter-
val (FR-30, FI-600 sec) components. PCD has
also been shown to have effects similar to those
of amphetamine on Fl performance in the
squirrel monkey (L. Byrd, personal communica-
tion).
The purpose of the present study was to
determine the effects of PCD and KT on re-
sponding under a mult FR-30 FI-300 sec sched-
ule of food presentation in the mouse. This
schedule was adopted because it has proved
useful in determining drug effects in other
species. Consequently comparison of the mouse
with other species could be made in order to
assess the usefulness of the mouse in behavioral
pharmacology. To aid in this assessment, d-
amphetamine and pentobarbital, which have
been extensively studied in other species, were
studied as reference drugs. The patterns of
responding observed in the mouse on the mult
TOP VIEW
SIDE VIEW
FR-30 FI-300 sec schedule were similar to those
observed with other species and other responses
under this schedule of reinforcement. The ef-
fects of d-amphetamine, PCD and KT in the
mouse were similar to the effects in the pigeon,
whereas there were differences in the effects of
pentobarbital.
Methods
Subjects. Male C57BL type mice derived from aC57BL/6J strain were used. They weighed approxi-mately 30 g when given free access to food and water.
Throughout the experiment they were maintained at75% of their free feeding weight. None of the mice had
been previously trained. Six mice (designatedM-47 to M-52) were used in the PCD study, three
mice (designated M-67 to M-69) in the KT study, andtwo mice each in the pentobarbital and d-ampheta-
mine studies (designated M-59, M-60 and M-61,M-62, respectively). The mice were housed in the
open laboratory, and testing was conducted during
the normal working day.
MICE
618 WENGER AND DEWS Vol. 196
Apparatus. The experimental chamber was a mod-
ified polypropylene mouse cage measuring 18 cm x 28
cm x 12 cm high (fig. 1). At one end ofthe chamber a
partition was installed creating a blind corridor 3.5cm wide and 5 cm long. At a point 0.5 cm from the endof the corridor a photocell was installed 1.2 cm from
the floor of the chamber in one of the side walls of the
corridor. At the corresponding point in the oppositewall a light source was mounted so that a beam of
light crossed the width of the corridor to strike thephotocell. An interruption of the light beam to the
photocell was recorded as a response. Directly below
the light beam was an opening in the floor (1 cm in
diameter) through which the mouse was given 3-
second access to a 0.025 ml dipper of evaporated milk.
On the wall at the end of the corridor at a point 4 cm
from the floor, a translucent plastic circle 1.2 cm in
diameter was mounted as a stimulus panel. The circlewas transilluminated by a 7.5 w green bulb during the
appropriate schedule component. In addition, an
electromechanical relay was installed on the side ofthe chamber which was operated four times per
second to make a clicking noise during the appropri-
ate schedule component. A second relay, operated
on interruption of the photocell beam, producedauditory feedback for each response. The experimen-
tal chamber was placed inside a sound attenuatingchamber; a 7.5 w bulb, in series with a 1000 ohm
resistor, illuminated the chamber at all times except
during the dipper presentation, producing a very low
level of illumination. Standard relay programmingand recording apparatus were used.
Procedure. A multiple FR-30 FI-300 sec schedule
of food presentation has been described in detail by
Ferster and Skinner (1957). In addition, Dews and
Morse (1958) and Morse (1962) have discussed the
application of the schedule to behavioral pharmacol-
ogy. In the presence of a distinctive stimulus, thegreen light in this experiment, 30 responses resulted in
access to the dipper of evaporated milk (FR-30). In
the presence of a different stimulus, the clicking relay
in this experiment, responding was maintained byaccess to the dipper of evaporated milk upon a
response at the end of the 300-second interval
(FI-300 sec). The schedules and their associatedstimuli alternated throughout the session. If 30 re-
sponses were not completed within 120 second in the
presence of the green light (FR), the schedule
changed; the light was turned off, and the clickingrelay started (Fl). If no response occurred within 30second after the 300-second interval had elapsed, theschedule changed back to FR. The session terminated
after 20 component changes had occurred (about 50
minute).
Training. Training was standardized for all mice,
and no manual shaping of the response was requiredon the part of the experimenter. The mouse wasdeprived of food until a body weight equivalent to 75%
of the free feeding weight was obtained. Typically the
desired weight loss was achieved in 2 to 3 days of fooddeprivation. The mouse was placed in the experimen-
tal chamber with a FR-i schedule in effect; a singleinterruption of the light beam onto the photocell
produced access to a dipper of evaporated milk. For
the first session, the dipper remained in the upposition for 10 second; in subsequent sessions the
dipper remained in the up position for only 3 second.Over the next 3 days, the FR response requirementwas increased to FR-30, and high rates (> 1.0 re-
sponses/sec) were maintained at each FR value. On
day 5, a mult FR-30 FI-300 sec schedule of food pres-entation was in effect. Stable performance wasachieved after about 12 sessions under this schedule
of food presentation.
Drugs. The drugs used were phencyclidine hydro-
chloride (Sernylan, BioCeutics Laboratories, St. Jo-
seph, Mo.), ketamine hydrochloride (Vetalar, Parke,
Davis and Company, Detroit, Mich.), pentobarbitalsodium (Abbott Laboratories, North Chicago, Ill.)
and d-amphetamine sulfate (Smith, Kline andFrench Laboratories, Philadelphia, Pa.). Phencycli-
dine hydrochloride and ketamine hydrochloride were
diluted with saline to the appropriate concentration.Pentobarbital sodium and d-amphetamine sulfate
wI-
LiJ��cr
crz
0
mg/kg d-AMPHETAMINE
FIG. 2. Effect ofd-amphetamine on the average rateof responding in each component of the mult FR-30FI-300 sec schedule. Abscissa: dose in milligrams perkilogram of body weight on a log scale; ordinate: ratioof the average rate after drug administration to theaverage rate on nondrug control days. Vertical lines atC represent the mean plus or minus 2 standard errorsof the control. The solid horizontal line represents themean control value. Each point represents the meanof single determinations in each of two mice. Meancontrol rates of responding were 0.62 responses/secand 1.40 responses/sec for the F! and FR, respectively.
M-61 M-6O
CONTROL
U)LiiC,)
a.U)Lii
000
30 mg/kg PENTOBARBITAL
V/v�
1976 PHENCYCLIDINE, KETAMINE AND BEHAVIOR 619
were dissolved in saline. All drug concentrations were
made so that the desired dose could be given in a
volume of 1 ml/100 g b.wt. All drugs were adminis-
tered by i.p. injection 300 second before the beginning
of the session; all doses are expressed as the salt. The
dose ranges studied were: PCD, 0.3 to 30 mg/kg i.p.
(1.25-125 ��mol/kg); KT, 1 to 180 mg/kg i.p.
(3.68-662.4 �mol/kg); d-amphetamine, 0.1 to 30mg/kg i.p. (0.27-81 �tmol/kg); and pentobarbital, 1 to
30 mg/kg i.p. (4.03-226 �smol/kg).
Drug injections were made once per week; the datacollected on the previous day served as the noninjec-
tion control.Measurement of drug effects. Average rates of
responding were computed as responses per secondfrom digital counters and elapsed time meters sepa-
rately for the FR and F! components. Results are
expressed as a ratio of the rate of responding on drugdays to the rate of responding on control days. For
analysis of rate dependencies, the Fl was divided into
10 equal segments. The responses in correspondingsegments of each interval were accumulated for theentire session, and a mean rate of responding wasdetermined for each segment. In addition, the meanrate of responding in the FR component was calculat-
ed. The mean rate of responding in each segment of
the F! and the mean rate of the FR on drug days were
expressed as a ratio of the response rate after drugadministration to the control rate in the correspond-
ing segment of the Fl and the FR. The ratio was
plotted on a log-log plot as a function of the control
rate of responding (Dews, 1964).
Results
The mult FR-30 FI-300 sec schedule engen-
dered patterns of responding similar to those
seen with other responses in other species
(Ferster and Skinner, 1957; Dews, 1955). Per-
formance in the FR component is characterized
by a very short initial pause averaging 1.7
second, followered by a continuous rate of
responding at more than 1.5 responses/sec.
Performance in the Fl component comprised an
initial pause much longer than under the FR,
followed by gradually accelerating responding
until the presentation of the food. Mean rate of
responding in the Fl was 0.73 responses/sec.
d-Amphetamine produced a dose-related de-
CONTROL
3 mg/kg �-AMPHETAMlNE
�
10 mg/kg g-AMPHETAMINE
600 SECONDS
FIG. 3. Cumulative response records of the performance of mice M-6i and M-60 under the mult FR-30 FI-300sec schedule showing typical control performances, the effect of two doses of d-amphetamine and two doses ofpentobarbital. Diagonal marks on the response pen line indicate the presentation of evaporated milk.Downward deflections of the lower horizonal line indicate the occurrence of the FR component of the multipleschedule. The pen automatically resets after 1000 responses and at the end of the session.
WENGER AND DEWS Vol.196
I 50
25
MICE
Li
LiJ�
0
0.75
0.50#{149} #{149}F1300
0---�0 FR3O
0.25
\
620
crease in FR response rates, and a biphasic
effect (increase at low doses and decrease at
high doses) on Fl response rates (fig. 2). The
response rate in the FR component was de-
creased at lower doses than those necessary to
decrease average Fl response rate.
The effect of two doses of d-amphetamine on
the performance of one mouse (M-6i) is seen in
the representative cumulative response records
shown in figure 3. The most striking feature
observed was the large increase in the Fl re-
sponse rate, especially in the early portions of
the Fl. The drug-induced changes in Fl re-
sponding were dependent on the control rate of
responding: low rates were increased more than
high rates. By inspection of the cumulative
record, at 10 mg/kg the rate of responding
during the period of FR responding was de-
creased with no obvious change in the pause
before the start of the FR responding.
The effects of pentobarbital on both FR-30
and FI-300 sec performances were dose depend-
ent (fig. 4) and both components were similarly
affected; response rates were increased at low
doses and decreased at high doses. The dose
producing the maximum increase in Fl respond-
LiLii�
0
0 - __C NaCI 0.3 I 3 0 1 30
8
mg/kg PHENCYCLIDINE HCI
.50
MICE MICE
#{149} #{149}F1300
0-- -o FR 30
to0
C I 3 013018 56mg/kg PENTOBARBITAL
C I 3 0 30H00156 180
mg/kg KETAMINE - HCI
FIG. 4. Effect of pentobarbital on the average rate ofresponding in each component of the mult FR-30F1-300 sec schedule. The data are expressed as infigure 2. Each point represents the mean of singledeterminations in each of two mice. Mean controlrates of responding were 0.82 responses/sec and 1.48responses/sec for the F! and FR, respectively.
FIG. 5. Effects of PCD on the average rate ofresponding in each component of mult FR-30 FI-300sec schedule. The data are expressed as in figure 2.Each point represents the mean of single determina-tions in each of six mice. Mean control rates ofresponding were 0.74 responses/sec and 1.43 re-sponses/sec for the Fl and FR, respectively.
FIG. 6. Effects of KT on the average rate ofresponding in each component of the mult FR-30FI-300 sec schedule. The data are expressed as infigure 2. Each point represents the mean of singledeterminations in each of three mice. Mean controlrates of responding were 0.68 responses/sec and 1.60responses/sec for the F! and FR, respectively.
M-49 M-69
CONTROL
U)wU)z0a.U)Lii
000
30 mg/kg KETAMINE
100 mg/kg KETAMINE
A A
/� /1 �11
1976 PHENCYCLIDINE, KETAMINE AND BEHAVIOR 621
CONTROL
VVH10 mg/kg PHENCYCLIDINE
8 mg/kg PHENCYCLIDINE
:1
600 SECONDS
FIG. 7. Cumulative response records of the performance of mice M-49 and M-69 under the mult FR-30 FI-300sec schedule showing typical control performances, the effect of two doses of PCD and two doses of KT.Diagonal marks on the response pen line indicate the presentation of evaporated milk. Downward deflections ofthe lower horizontal line indicate the occurrence of the FR component of the multiple schedule. The penautomatically resets after 1000 responses.
ing also produced the maximum increase in FR
responding.
In figure 3 representative cumulative records
are also shown for one mouse (M-60), showing
control and two doses of pentobarbital. Pento-
barbital had a marked effect on the F! pattern
of responding. Responding in early portions of
the Fl was increased more than responding in
the terminal portions, resulting in a more nearly
constant response rate in the Fl component at
doses of 3 mg/kg and higher, at the time of peak
effect. The changes in the rate of responding
induced by the drug were rate-dependent in
that low rates were increased proportionately
more than high rates. At the highest dose
studied, 56 mg/kg, not shown, responding was
completely suppressed for most of t�ie session.
When responding started, the effect of pento-
barbital appeared to be the same in both
components.
PCD had qualitatively similar effects to KT
on the responding maintained by the mult
FR-30 FI-300 sec schedule (figs. 5 and 6). Both
produced a dose-related decrease in responding
in the FR component. The doses of PCD and
KT which decreased response rates in the FR
component were lower than the doses required
to decrease average Fl response rates. The effect
of PCD and KT on the Fl response rate was
biphasic. At low doses the Fl response rate was
increased, and at higher doses the Fl response
rate was decreased.
Figure 7 shows representative cumulative
records of responding in two mice under con-
trol conditions and after two doses of PCD or
two doses of KT. The effect of PCD and KT
on the F! component is to increase responding in
the early portions of the Fl. This produces the
nearly constant rate of responding observed at
the time of peak effect with 10 mg/kg of PCD
and at 30 mg/kg of KT. The mean rate of
responding under the FR component is de-
creased by PCD and KT without an apparent
increase in pause time before the start of the FR
responding.
That the effect of PCD and KT on Fl re-
sponding is dependent on the corresponding
control rate of responding is seen in figures 8
and 9. With PCD (fig. 8), low control rates of
responding are increased while higher control
00
#{163}
622 WENGER AND DEWS Vol.196
10.0
Lii 3.0‘Li4
00
0
0.3
M -48
PHENCYCLI DINE
0-o 3 mg/kg
#{149} #{149}10 mg/kg
M-49
0 -‘
0.1 0.3 1.0 3.0 0.1 0.3 1.0 3.0
CONTROL RATE CONTROL RATE
FIG. 8. Dependence of the effect of PCD on the control rate of responding in mice M-48 and M-49. Abscissa:average rate of responding on a log scale in successive 30-second periods of the F!-300 sec schedule (circles), andunder the FR-30 response schedule (triangles); ordinate: ratio of the average rate after drug administration tothe average rate on nondrug control days. Open symbols (circles and triangles) represent the effect of 3 mg/kgi.p. of PCD; closed symbols represent the effect of 10 mg/kg i.p. of PCD.
rates of responding are either unchanged (3
mg/kg) or, as seen at 10 mg/kg, decreased. The
same qualitative relationship is seen with KT
(fig. 9). Figures 8 and 9 show also that the points
for the FR performance lie below the regression
line of rate dependence drawn through the F!
data points.
Discussion
Interruption of a light beam striking a photo-
cell is a response easily acquired by mice
without the necessity of individual “shaping”
by the experimenter. Training can thus be
standardized. Also, the large numbers of sub-
jects necessary for some lines of work could be
trained without the labor becoming prohibitive.
Stable performance is achieved rapidly on a
schedule such as mult FR-30 FI-300 sec, and the
pattern of responding is very similar to other
species and other responses. The behavior
maintained by the mult FR-30 FI-300 sec sched-
ule in the mouse rapidly comes under stimulus
and schedule control, as seen in the cumulative
records.
The effects of d-amphetamine on the behav-
ior of the mouse are similar to the effects
reported for other species responding on similar
schedules. d-Amphetamine produced a dose-re-
lated decrease in the FR response rate, and
a biphasic (increase followed by a decrease)
effect on response rates in the Fl. The FR
behavior appeared to be more sensitive to the
rate decreasing effects of d-amphetamine than
did the Fl behavior. In addition, the rate
increases seen in the Fl were of the rate-depend-
ent type: low rates were increased more than
high rates. These effects are similar to the
effects of d-amphetamine on pigeons pecking a
pigeon key (Smith, 1964; Rutledge and Kelle-
her, 1965; McMillan, 1968, 1969), rats pressing
a lever (Clark and Steele, 1966) and monkeys
pressing a lever (Cook and Kelleher, 1962;
Kelleher and Morse, 1964).
The effect of pentobarbital on the perform-
ance of mice on this schedule is similar to that
reported for barbiturates in pigeons (Rutledge
and Kelleher, 1965; Morse, 1962; Leander and
McMillan, 1974; McKearney, 1972) and mon-
1976 PHENCYCLIDINE, KETAMINE AND BEHAVIOR 623
M-67 M-68
KETAMINE
0-o 30 mg/kg
#{149}#{149}56 mg/kg
0.0
3.0
0
.0
0.3
#{163}
00.1 0.3 1.0 3.0 0.1 0:3 .0 3.0
CONTROL RATE CONTROL RATE
FIG. 9. Dependence of the effect of KT on the control rate of responding in mice M-67 and M-68. The data areexpressed as in figure 8. Open symbols (circles and triangles) represent the effect of 30 mg/kg i.p. of KT; closedsymbols represent the effect of 56 mg/kg i.p. of KT.
keys (Verhave, 1959) on multiple Fl FR
schedules, except that the greater sensitivity of
F! over FR in responding to the rate-decreasing
effects of the barbiturates was not observed.
The behavioral effects of PCD and KT are
similar to those seen recently in the pigeon
(Wenger, 1976). Both drugs produced a biphasic
(increase followed by decrease) effect on the Fl
response rate. The amount of increase or de-
crease in rate depended on the control rate of
responding: low rates of responding were in-
creased more than high rates of responding. The
behavior maintained by the FR component in
the mouse was decreased by both PCD and KT
in a dose-related manner. The FR rate was
decreased more than would have been predicted
on the basis of the changes produced by the
drug in Fl responding (figs. 8 and 9). The
different effects of the drugs on responding
under the FR and under the Fl were not
exclusively dependent on the average rate of
responding.
PCD and KT increased responding main-
tamed by the F! component at doses which
decreased the responding maintained by the FR
(figs. 5 and 6). The maximum increase in Fl
response rates occurs at a dose of d-ampheta-
mine which does not affect the average FR
response rate (fig. 2). Pentobarbital produces a
maximum increase in F! response rates at the
same dose which produces the maximum in-
crease in the FR response rates (fig. 4). These
differences appear to be drug-specific effects.
PCD, KT and d-amphetamine increase spon-
taneous motor activity as measured by jiggle
cages (Schulte et a!., 1941; Chen et a!., 1959,
1966). More recent work counting photocell
crossings has confirmed the earlier results
(Smith, 1963; Rolinski and Scheel-Kr#{252}ger, 1973;
Villarreal et al., 1973; Thornburg and Moore,
1973; Glick and Milloy, 1973; Hittzemann et al.,
1973). Although the response used in this study
was also the breaking of a light beam striking a
photocell, the dose-response relationships are
different from those seen with “spontaneous”
motor activity. Hittzemann et a!. (1973) re-
ported a dose-dependent increase in motor ac-
tivity in mice given PCD with a maximum
increase at 10 to 30 mg/kg i.p. In the present
study, the maximum increase in the response
rate in the F! component was observed after 3
mg/kg i.p. PCD. Doses higher than 3 mg/kg of
624 WENGER AND DEWS Vol.196
PCD decreased the schedule-controlled re-
sponse rate. Similarly, d-amphetamine pro-
duces dose-related increases in motor activity
with the maximum effect observed at 5 to 10
mg/kg i.p. (Smith, 1963; Rolinski and Scheel-
Kruger, 1973; Villarreal et a!., 1973; Thronburg
and Moore, 1973; Glick and Milloy, 1973; Hitt-
zemann et a!., 1973) which is also higher than
the dose of d-amphetamine producing the max-
imum increase in F! responding in the present
study.
In summary, PCD and KT have been shown
to have very similar effects in the mouse on a
mult FR F! schedule of food presentation. The
effects are generally similar to those seen in the
pigeon. The effects of d-amphetamine are also
similar to those reported in a variety of other
species on similar schedules; pentobarbital
showed differences in that F! and FR respond-
ings were similarly affected, but more work is
necessary to determine whether the difference is
due to species differences, response differences
or other factors.
Acknowledgments. The authors would like
to thank Drs. W. H. Morse and R. T. Kelleher
for helpful comments and Margery Schwartz
and Carolyn Mosher for help in the preparation
of this manuscript.
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